Despite significant efforts cocaine abuse remains a continuing public health problem. Chronic cocaine use is accompanied by neuroadaptations in multiple neurotransmitter systems, as well as enduring changes in brain functional activity. To date there are no FDA approved medications for treatment of cocaine dependence. Drug development efforts are hampered by the lack of understanding of the neurobiological basis of potential pharmacotherapeutic strategies. The goal of these studies proposed is to characterize at a systems level the neurobiological effects of potential treatment drugs that have shown positive signals in current clinical trials, drugs approved for use In humans being considered for use in treatment; and mechanistic drug treatments for which preliminary animal studies suggest may be useful in reducing cocaine reinforcement based on their mechanisms of action. The convergence of Information from these different strategies will provide critical Information about the neuropharmacological mechanism of effective treatment and guide future drug development. Aim 1 will evaluate the consequences of chronic administration of candidate medications and then assess the neurobiological effects of these medications in rodent models of chronic cocaine self-administration in neurochemical systems as established in Project 1 We will measure changes in the function of dopamine systems using microdialysis in freely moving rats and voltammetry in brain slices and assess changes in functional brain activity with the 2-deoxyglucose method and the expression of immediate early genes consequent to chronic treatment with candidate medications. Aim 2 will make use of established nonhuman primate models of cocaine self-administration to evaluate the consequences of these potential pharmacotherapies on brain transmitter systems and to characterize the sites of changes in functional activity accompanying responses to cocaine-associated cues and cognitive processes as established in Project 1 It is only through a systems level analysis with clinically relevant models of substance abuse as proposed in this application that a greater understanding of the neurobiological basis of treatment can emerge. Thus, the systems approach of Project 2 provides a bridge between behavioral evaluations in Project 1 and the cellular approaches in Project 3.